The long term objectives are to understand the regulation and function of wound insulin-like growth factor-I (IGF-1) and IGF binding protein (IGFBP) levels during tissue repair, and also to use this knowledge to modulate tissue repair in disease states. In this project, our knowledge of IGF-I will be expanded by in vivo and in vitro studies. Experiments will be initiated to understand the mechanisms of IGF-I actions in wounds and how IGF-I may be involved in pathological states of repair and trauma. In Aim 1 human fibroblasts will be used to investigate whether IGF_1 phosphorylates nuclear poly(ADP-ribose) (PADPR) synthetase thereby inhibiting its activity and stimulating collagen gene expression. Whether the inhibitory effect of IGF-I on PADPR synthetase increases the cellular level of cyclic ADP-ribose will be examined in Aim 2. Cyclic ADP-ribose induces the release of intracellular calcium and could explain this same effect of IGF-I. Investigations into the role of IGF-I in glucocorticoid impaired wounds will be pursued to learn more about the interrelation of lactate, TGFb, vitamin A and inflammation in tissue repair. The second part of this grant deals with the actions and levels of IGF-I, IGFBPs, and IGFBP proteases in normal and pathologic wounds. Aim 4 will examine whether the IGF-I gene is over-expressed or IGFBPs are decreased in wounds characterized by increased collagen synthesis, hypertrophic scars and keloids. IGF-I and IGFBP-3 will be assayed by immunohistochemical techniques. Aim 5 will investigate in a rat model the role of IGF-I and IGFBPs in the formation of abdominal adhesions. The ultimate goal of Aims 4 and 5, if IGF-I were shown to have a pathological role, would be to block its action by an inhibitory IGFBP. The ability of IGFBP-3 to inhibit increased IGF-I activity and modulate tissue repair will be investigated in both Aims 4 and 5. In patients with trauma, head injury and burns the plasma IGF-I, IGFBPs, and IGFBP proteases will be determined in order to establish the relationship of abnormal levels to several parameters including the catabolic state, wound healing, infection, hospital stay and recovery.